Objective evaluation of changes in left ventricular and atrial volumes during parabolic flight using...

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OBJECTIVE EVALUATION OF CHANGES IN LEFT VENTRICULAR AND ATRIAL VOLUMES DURING

PARABOLIC FLIGHT USING REAL-TIME THREE-DIMENSIONAL ECHOCARDIOGRAPHY

E.G. Caiani1, L. Sugeng2, L. Weinert2, A. Capderou3, R.M. Lang2, P. Vaïda4

1 Dipartimento di Bioingegneria, Politecnico di Milano, Milan, Italy 2 Noninvasive Cardiac Imaging Laboratory, University of Chicago, Chicago IL, USA 3 Université Paris Sud, UPRES EA 2397, CCML, Physiologie, Le Plessis Robinson, France 4 Université Bordeaux 2, Médecine Aérospatiale, Bordeaux, France

Short title: RT3DE during parabolic flight

Address for correspondence:

Enrico G Caiani, PhD

Politecnico di Milano, Dipartimento di Bioingegneria

Piazza L. da Vinci, 32, 20133 Milano, Italy.

Tel: +39-02-2399-3302, Fax: +39-02-2399-3360;

E-mail: [email protected]

of 34 Articles in PresS. J Appl Physiol (April 6, 2006). doi:10.1152/japplphysiol.00014.2006

Copyright © 2006 by the American Physiological Society.

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Abstract

Objectives. We tested the feasibility of real-time 3D echocardiographic (RT3DE) imaging

to measure left heart volumes at different gravity during parabolic flight and studied the effects of

lower body negative pressure (LBNP) as a countermeasure. Background. Weightlessness-

related changes in cardiac function have been previously studied during space flights using both

2D and 3D echocardiography. Several technical factors, such as inability to provide real-time

analysis and the need for laborious endocardial definition have limited its usefulness. RT3DE

imaging overcomes these limitations by acquiring real-time pyramidal datasets encompassing

the entire ventricle. Methods. RT3DE datasets were obtained (Philips 7500, X3) during breath-

hold in 16 unmedicated normal subjects in upright standing position at different gravity phases

during parabolic flight (normogravity, 1Gz; hypergravity, 1.8Gz; microgravity, 0Gz), with LBNP

applied (-50 mmHg) at 0Gz in selected parabolas. Results. RT3DE imaging during parabolic

flight was feasible in 14/16 subjects. Data were analyzed (Tomtec) to quantify left ventricular

(LV) and atrial (LA) volumes at end-diastole and end-systole, which significantly decreased at

1.8Gz and increased at 0Gz. While ejection fraction did not change with gravity, stroke volume

was reduced by 16% at 1.8Gz and increased by 20% at 0Gz, but was not significantly different

from 1Gz values with LBNP. Conclusions. RT3DE during parabolic flight is feasible and

provides the basis for accurate quantification of LV and LA volume changes with gravity. As

LBNP counteracted the increase of LV and LA volumes caused by changes in venous return, it

may be effectively used for preventing cardiac dilatation during microgravity.

Keywords: real-time three-dimensional echocardiography, weightlessness, parabolic flight,

countermeasures

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Introduction

During space flight, changes in gravity (Gz, head-to-foot acceleration) affect the

cardiovascular system by causing fluid shifts from the lower extremities toward the head and

thorax, thus altering central filling volumes and pressures (15; 16; 23; 31). These hemodynamic

alterations, which directly influence heart chamber dimensions and function, are responsible for

many of the adverse effects associated with the post-flight orthostatic intolerance observed in

astronauts (20-22).

The potential for commercial spaceflight has made a precise understanding of the early

cardiovascular adaptation to weightlessness important. As more individuals have the opportunity

to fly in space, standards will need to be set to decide what level of cardiovascular function is

needed to tolerate the acute headward fluid shift that occurs in weightlessness. Some individuals

with non-distensible ventricles potentially could develop pulmonary edema upon entering

weightlessness. Measurements of the expected changes in ventricular volumes, atrial volumes

and peak filling rate upon entering weightlessness are needed to help set appropriate standards.

In addition, certain countermeasures, like lower body negative pressure (LBNP) devices (24;

38), could be used to reduce the fluid shift and prevent or treat adverse events.

Moreover, the evaluation of cardiovascular physiology under different gravitational loads

may provide some crossover benefits to clinical medicine on Earth. Ground-based studies

represent an invaluable opportunity to investigate human physiology during simulated

microgravity conditions. Among them, parabolic flight presents an unique opportunity to study

the immediate physiological adaptations of the cardiovascular system to different gravity

conditions.

Two-dimensional echocardiography (2DE) has been the principal imaging modality used

in space programs to evaluate changes in the cardiovascular system, and to test the

effectiveness of countermeasures employed to alleviate these changes (34). Using 2DE,

patterns of adaptation of left ventricular (LV) dimensions to microgravity during short- and long-

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term missions have been previously described (3; 10; 11; 25; 37; 41). However, although 2DE is

routinely used in clinical practice to measure heart chamber dimensions, wall thickness, and

function, this imaging technique is limited because it relies on correct probe positioning to avoid

acquisition of foreshortened apical views. In addition, derivation of volumetric parameters from

multiple 2D views requires the use of geometric models which may introduce additional errors

(19; 43; 49).

In an attempt to circumvent these constraints, Zoghbi et al. have developed a non-

geometric three-dimensional echocardiographic (3DE) method by acquiring multiple short-axis

2DE images of the LV from a single pivoting point and reconstructing the volume off-line (50).

Using this approach, 3DE was previously used in space (Spacelab Life Sciences-1 and –2

missions), to measure LV volumes (8). However, this methodology is limited by several factors,

such as cumbersome data acquisition required for off-line 3D reconstruction and the need for

tedious off-line manual tracings of endocardial borders in multiple planes.

The recent development of second generation full-matrix array transducers, capable of

high spatial resolution and near real-time acquisition of wide-angled pyramidal 3D

echocardiographic datasets, has overcome many of the limitations of 2DE, and thus provided

the basis for accurate estimates of LV volumes (13; 26; 30), mass (36) and function (18).

We hypothesized that real-time 3D echocardiography (RT3DE) could be used in a

weightlessness environment for accurate quantification of the adaptations in LV and left atrial

(LA) dimensions in response to changes in gravity. Accordingly, the aims of this study were: 1)

to test the feasibility of RT3DE imaging of the left ventricle and left atrium in a weightlessness

environment; 2) to evaluate the changes in LV and LA volumes occurring with changes in gravity

during parabolic flight; 3) to test the effectiveness of the LBNP device in reducing LV and LA

volumes during microgravity by counteracting the decrease in hydrostatic pressure in the lower

body.

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Methods

Subjects.

Eighteen normal volunteers (13 men and 5 women, mean age 38 ± 14 years) without a

history of cardiovascular disease were enrolled in the study, after providing written informed

consent. All subjects were screened prior to participation to ensure adequate acoustic windows

even when imaging in the upright position. After completion of the preliminary screening, sixteen

out of the eighteen volunteers (12 men and 4 women, mean age 36±13 years) were selected.

None of the subjects were taking medication prior to and/or during the flights. This study was

approved by both the French (Centre National d’Etudes Spatiales - CNES) and the European

Space Agency (ESA).

Equipment and protocol.

The study was conducted during two parabolic flight campaigns (CNES - November

2004, ESA – October 2005), on board of the ESA - CNES ZeroG Airbus A300 aircraft,

performed in Bordeaux, France Each flight lasted 2.5–3 hours and included 31 parabolas.

Instantaneous gravity was continuously measured using the aircraft’s accelerometer.

Gravity variations during a parabolic flight trajectory include four consecutive phases (Figure 1,

left): normogravity (phase I: head-to-foot acceleration 1 Gz) prior to parabola initiation; mild

hypergravity (phase II: 1.8 Gz, 20 sec) during the ascending phase of the parabola; microgravity

(phase III: 0 Gz, 24 sec), at the top of the parabola; a second period of mild hypergravity (phase

IV: 1.8 Gz, 20 sec) during the descending phase of the parabola. Between consecutive

parabolas, a period of steady state (at 1 G) persisted for a minimum of two minutes.

Each subject was imaged in the upright standing position during a maximum of 12

consecutive parabolas, with the abdomen and lower extremities placed inside a LBNP chamber

(Figure 1, right). To allow the lower limbs to stay relaxed (to maximize blood and fluid movement

to/from the lower body), subjects were placed on a saddle within the LBNP chamber with the

arms secured to the structure by straps. To test the effectiveness of LBNP in counteracting the

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effects of microgravity by reducing venous return, a negative pressure of –50 mmHg was applied

during the 0Gz phase in selected parabolas (from 3 to 5) in random order.

Real-time 3D echocardiographic imaging

Transthoracic RT3DE was performed from the apical window, with a full-matrix array

transducer (X3, 2-4 MHz) in the harmonic mode using a SONOS 7500 (Philips Medical Systems,

Andover, MA). To avoid body movement during acquisition, both subject and sonographer were

stabilized against free floating. A second operator aided in optimizing image quality (gain and

compression) and completing data acquisition.

For each gravity phase of the parabola, one RT3DE dataset representing one cardiac

cycle (frame rate 20 Hz) was acquired during a breath-hold, while avoiding Mueller or Valsalva

manoeuvres, and thus trying to minimize changes in intrathoracic pressure. Image acquisition

was performed using the wide-angled acquisition mode, in which four wedge-shaped sub-

volumes (93°x21°) were obtained over eight cardiac cycles with ECG gating. In this mode, each

sub-volume acquisition is triggered to the R-wave of every other heart beat in order to allow

sufficient time for the probe to be recalibrated and each sub-volume stored. Particular care was

taken to include the entire left ventricle and atrium within the pyramidal 3D scan volume.

Image acquisition at 1Gz was performed 10 sec prior to the initiation of phase II, while

image acquisition at 1.8Gz, 0Gz and final 1.8Gz were performed 5 sec after the beginning of

phase II, III and IV, respectively, to avoid data acquisition during the short initial transition during

which abrupt changes in cardiac volumes and heart rate may occur.

RT3DE volume analysis

The RT3DE datasets acquired in each subject during each phase of the parabola (i.e., I,

II, III and IV) were first visually inspected. Only parabolas with proper LV and LA endocardial

visualization in each gravity phase, assessed in two orthogonal cut-planes, corresponding to

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apical 2- and 4-chamber views, were selected for analysis. The RT3DE datasets were analyzed

in random order by an expert reader, blinded to the subject’s identity and to the gravity phase.

To quantify LV dimensions, each dataset was analyzed off-line using commercially

available software (4D LV Analysis, TomTec), previously described in detail (30). Briefly, after

identifying the LV long-axis, six equi-angled long-axis cut-planes were automatically generated

(Figure 2, A). To define the mitral valve plane in each of these cut-planes, the mitral valve

annulus was identified in the end-diastolic (ED) and end-systolic (ES) frames. An ellipse was

then placed in the ED and ES frames in each of the six selected long-axis cut-planes, manually

adapting its shape and angular position to fit as close as possible to the endocardial border.

Following this initialization phase, the semi-automatic endocardial contour detection procedure

was applied, resulting in a detected endocardial contour for each cut-plane and for each

consecutive frame throughout the cardiac cycle (Figure 2.B). In order to verify the correctness of

the border detection, each cut-plane was then visualized in the cine mode with the detected

contour overimposed, to allow the operator to perform manual adjustments, when necessary.

Finally, for each frame, the contours of the six cut-planes were then interpolated and displayed

as a wire-frame model in the 3D space (Figure 2.C), from which the enclosed LV volume was

computed using Gaussian quadrature formulas.

Global LV volume versus time curves were obtained, from which end-diastolic (EDV) and

end-systolic (ESV) volumes, defined as the maximum and the minimum volume, respectively,

were measured. Stroke volume (SV) was computed as the difference between EDV and ESV,

and ejection fraction (EF) was derived as 100* SV/EDV. Moreover, the first derivative of LV

volume versus time was computed, and the peak filling (PFR) and peak ejection (PER) rates

calculated.

To quantify the LA volumes in the ED and ES frames, the same RT3DE datasets were

analyzed off-line using commercial software (EchoView, TomTec). After selecting the LA long

axis, 8 equi-angled 2D long-axis cut-planes were generated (Figure 3.A), and in each pair of

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orthogonal planes, manual tracing of the atrial endocardial borders was performed using an

interactive spline interpolation algorithm (FIgure 3.B-C). After interpolation of the traced contours

in a 3D wire-frame model (Figure 3.D), the LA cavity volume was calculated automatically (29).

The LA volume computed in the ES frame was defined as LAmax, while the LA volume

computed in the ED frame was defined as LAmin. The LA reservoir function was assessed using

filling volume (FV), defined as (LAmax − LAmin), and the expansion index (EI), defined as

100*FV/LAmin. The overall diastolic emptying index (DEI) was calculated as 100*FV

/LAmax*100 (44). Moreover, to evaluate possible asymmetries in LA shape changes with

microgravity, the LA diameters along its major (D2, antero-posterior dimension) and minor (D1,

medial-lateral dimension) axes were computed at 1Gz and 0 Gz.

Statistical analysis

LV and LA volumes and derived parameters, normalized by their value at 1Gz, were

averaged for all subjects in each gravity phase. Data were displayed as mean±SD. One-way

ANOVA with repeated measures (p<0.05, Tukey test) was used to test the differences between

gravity phases. The effectiveness of LBNP in reducing changes in LV, LA volumes and derived

parameters at 0Gz was tested by paired student’s t-test. Differences were considered significant

for p<0.05 compared with the results at 0Gz obtained without LBNP.

Results

RT3DE imaging during parabolic flight was feasible in 14/16 subjects (87.5% of success),

in which RT3DE datasets were acquired for each gravity phase (1Gz, first 1.8Gz, 0Gz, second

1.8Gz). In the remaining two subjects, adequate visualization of the LV during all gravity phases

of the parabola was difficult due to unpredictable shifting of the heart within the chest cavity. In

these subjects, repositioning of the probe required more time than the 20 sec available for image

acquisition during each phase of the parabola.

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Of these 14 subjects, only 10 had also the RT3DE datasets acquired during 0Gz with

LBNP activated. In the remaining 4/14 subjects, this data acquisition was non possible due to

subjects experiencing motion sickness (3/14), and due to flight interruption caused by weather

conditions (1/14).

Quantitative analysis of LV and LA chambers was feasible in all RT3DE datasets

selected for analysis. The time required to analyze a complete RT3DE dataset to compute the

LV volume was about 15 min, while the time required to analyze a single frame to measure the

LA volume was approximately 3 minutes. Results obtained from the analysis of up to three

parabolas in each subjects were averaged to take into account intra-subject variability.

Figure 4 shows LV volume versus time curves with the corresponding first derivatives

computed in a same subject during normogravity, hypergravity and microgravity. Compared to

the 1Gz curve, an upward shift of the LV volume curve was noted at 0Gz. In contrast, a

downward shift of the LV volume curve was seen at 1.8Gz. Also, an increase in PFR was

evident during microgravity. Figure 5 shows an example of the LV (top) and LA (bottom) 3D ED

and ES casts obtained in the same subject during the different phases of the parabola: during

hypergravity, a shrinking of both the left ventricle and atrium was observed compared to

normogravity, while an enlargement was seen during the microgravity phase.

Significant changes in both LV and LA volumes were measured during the different

phases of the parabola (Table 1). Compared to 1 Gz values, both ED and ES LV volumes

decreased by 19% and 24%, respectively, during hypergravity, and increased of 19% and 23%,

respectively, during microgravity. These changes resulted in a reduction of SV of 16% during

hypergravity and an increase of 20% during 0Gz, while EF did not change with gravity. Though

PFR and PER did not change at 1.8Gz, these parameters increased by 31% and 37%,

respectively, during microgravity, compared to1Gz values (Figure 6).

Compared to normogravity, both LAmax and LAmin volumes decreased by 34% and

29%, respectively, during hypergravity, and increased by 41% and 26%, respectively, during

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microgravity. As a consequence, filling volumes were reduced by 36% and increased by 59% at

1.8Gz and 0Gz, respectively. Both DEI and EI increased during microgravity by 12% and 31%,

respectively (Figure 7). Left atrial D1 and D2 diameters at end-systole were increased by 28%

and 18% at 0 Gz, while at end-diastole only D2 was found augmented by 25% compared to 1 Gz

(Table 2).

With the activation of the LBNP countermeasure during microgravity, LV and LA volumes

were quantified in 10 subjects. All LV and LA parameters trended towards 1Gz values (Figure 8),

resulting in an attenuation of the changes noted at 0 Gz without LBNP. In particular, EDV and

PFR were found reduced and restored to 1Gz values. Also, LAmax, FV and DEI were reduced

and not different from their values at 1Gz.

Discussion

This study is the first to provide three-dimensional echocardiographic datasets from

complete cardiac cycles in weightlessness, allowing for the calculation of LV and LA volumes

and performance data.

Cardiac ultrasound has been the only medical imaging modality used in space to

evaluate cardiovascular function. However, its use for scientific purposes during space flights

has been limited due to operational constraints and technical factors (34). Despite these

limitations, two-dimensional echocardiography has been used to measure changes in cardiac

size and function during weightlessness (37);(5);(3), and to assess the time course of post-flight

recovery (2; 6; 10; 25; 35).

Parabolic flights are the only way to reproduce in humans the weightlessness (or free-

falling) state which characterizes space flights, thus representing a unique experimental

condition to study reversible and repeatable acute non-pharmacologically induced variations in

venous return in the same subject. We demonstrated the feasibility of acquiring 3D datasets

suitable for analysis for each gravity phase of the parabola, despite the relatively short period of

time available for image acquisition. The methodology used in this study allowed us to overcome

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many of the limitations of 2DE imaging. In particular, the availability of a 3D pyramidal dataset

allowed off-line selection of the anatomically correct LV long-axis, from which the equi-angled

long-axis cut-planes were obtained for endocardial contour detection. This minimized LV apical

foreshortening thus preventing the underestimation of LV volumes. Also, the frame-by-frame

analysis throughout the cardiac cycle allowed computation of LV volume versus time curves,

from which clinical parameters, such as peak filling and ejection rates, were derived. From the

same datasets, we also measured the effects of microgravity on LA volumes, to obtain new

insights into the physiology of this chamber at 0Gz.

In contrast to other studies (27; 42; 48), imaging the subjects in the standing position allowed us

both to maximize the effects of abrupt gravitational fluid shift on LV and LA volumes and to

study, for the first time during parabolic flight, the effects induced by LBNP.

Our results demonstrate that, when a subject experiences a higher gravitational stress

(phase II, 1.8 Gz), both LV and LA volumes become smaller compared to 1Gz values, due to a

decrease in venous return, resulting in a reduction of SV and left atrial FV. Interestingly, during

the second hypergravity phase (phase IV) these parameters were also significantly reduced

compared to 0 Gz but not different from 1 Gz values. Since the left heart is more dilated at the

beginning of phase IV compared to the onset of phase II, the hypergravity induced reduction in

LV and LA volumes appears to be independent from the gravity gradient (+0.8 Gz in phase II

and +1.8 Gz in phase IV) and more directly related to the magnitude of the pre-existing LV and

LA volumes when entering the hypergravity phase.

In contrast, when the subject is in 0 Gz, both ED and ES LV volumes augment

approximately by 20% compared to 1Gz values, resulting in an increase in SV, while EF remains

unchanged. These LV volume changes have been previously shown to be due to the increase in

central blood volume that occurs in weightlessness. The increase in cardiac volumes occurs

despite a decrease in central venous pressure (48), potentially due to a reduction in intrathoracic

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pressure and/or to the loss of compressive forces that occurs throughout the body in

weightlessness.

In a previous study, where we measured LV area changes from 2DE in the apical 4-

chamber view using a similar experimental setting, we reported an increase in LV area at 0 Gz

of only 12% (17). Compared to the current results, the underestimation found with 2DE was

probably due to apical foreshortening, caused by the difficulties in continuously acquiring the

correct anatomical 2D plane during the parabola. Our observations on LV volume changes at 0

Gz induced by parabolic flight closely resemble the short-term effects of 0 Gz on LV dimensions

occurring in astronauts during the initial 2-3 days of space flight (9). This data reinforces the

notion that parabolic flight represents a unique setting to study the short-term effects of

weightlessness on Earth.

The observed increase in the rapid LV filling during 0Gz is in agreement with our

previous observation that a significant increase in the peak mitral E wave occurs in standing

subjects during microgravity (12) due to increased LV preload. The observed increase in PER

could be explained by both increased LV ED pressure caused by the EDV augmentation, and by

probable afterload reduction due to decreased blood pressure with microgravity (7; 42).

With regard to the left atrium, we found that at 0 Gz, both the ED and ES LA volumes

increased considerably compared to 1Gz values, resulting in an increase in both the LA

reservoir function (i.e., FV and EI) and in the overall diastolic emptying index. Previously,

Videbaek and Norsk studied the end-systolic LA diameter by M-mode from the parasternal long-

axis view in subjects in the supine position during parabolic flight (48), reporting a 15% increase

at 0 Gz compared to 1 Gz. The measurement of only a single diameter of the LA represented a

limitation of that study, because it assumed that a consistent relationship is maintained between

the antero-posterior and all other LA dimensions as the atrium enlarges, which is often not the

case (32; 33). Our results obtained with RT3DE measured the true atrial volume, and

demonstrated that the magnitude of LA distension at 0 Gz appears to be larger (approximately

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doubled) than previously reported. Moreover, changes in LA D1 and D2 diameters at 0 Gz

evidenced a similar increase of about 7mm in D1 and D2 at end-systole, demonstrating a

symmetric distension of the LA following an abrupt increase in venous return.

These findings could be considered for the formulation of new qualification criteria for

commercial space travel. Since the increase in venous return induced by microgravity generates

a considerable increase in LA and LV volumes, a compliant LV is required to avoid any abrupt

increase in filling pressures. Non-invasive manoeuvres resulting in significant preload

augmentation (i.e., -40° head-down tilt) could be used in the future to assure LV compliance. In

fact, we can hypothesize that, when entering weightlessness, individuals with compromised LV

compliance could develop pulmonary edema, resulting in different clinical scenarios, which could

range from a reduction of in-flight performance to a life-threatening condition.

Lower body negative pressure (LBNP) has been used as a test of orthostatic tolerance

both on Earth and during long-term space flights, and as an in-flight countermeasure prior to re-

entry, associated with fluid intake, to prevent post-flight orthostatic intolerance. Although

previous studies investigated the effects of LBNP on LV dimensions in various experimental

conditions using 2DE (4; 28; 39; 45; 46), this is the first time that LBNP has been studied during

parabolic flight, to assess in a weightlessness environment its counterbalancing effects on LV

and LA volumes in a normal heart. In ground experiments, performed in subjects in the supine

position, a reduction in LV volumes and SV with LBNP at different pressures (from –10 to –40

mmHg) have been previously reported using M-mode echocardiography (28; 39). Our results

obtained in subjects in standing position during 0 Gz showed that LBNP at –50 mmHg was able

to restore LV and LA dimensions to 1 Gz values, in particular LV EDV, LAmax and LA filling

volume. Since LBNP is known to increase the pooling of blood in the lower body, leading to

decreases in both central blood volume and cardiac filling pressures (1; 14; 40; 47), and since

microgravity has been shown to increase central blood volume and atrial distension (48), the

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combined effect of microgravity and LBNP appear to counterbalance each other resulting in

minimal change in central blood volume.

This study had several limitations. First, 3D echocardiography using a full-matrix array

transducer has been previously described as being a “real-time” technique. However, data were

acquired in the full volume mode, which is a “near” real-time technique that requires temporal

registration of a number of sub-segments acquired from consecutive beats. Accordingly, it was

not possible to acquire datasets representative of consecutive cardiac cycles along the whole

parabola, but only one dataset for each gravity phase. However, after the short transient when

entering in a new gravity phase, the LV and LA volumes can be considered stabilized and

representative of the corresponding parabolic phase. Furthermore, in the interpretation of the

results, when the effects of 1 Gz are compared with those of weightlessness, it is important to

consider the effects of the hyper-G phase occurring in between.

The semi-automated segmentation procedure requires to manually initialize the

endocardial borders in multiple evenly rotated long axis views, which is a time-consuming and

subjective procedure. Nevertheless, this technique, applied to the left ventricle, was found to be

highly reproducible and accurate (30). As no standard analysis methods for LA volume

quantification from RT3DE data exist, our measurements of absolute LA dimensions could be

affected by biases or inaccuracies. However, as these errors should be of the same magnitude

for each gravity phase, and since results were normalized in each subject for the corresponding

1Gz values, the resulting change in LA volumes should not be affected by the method of

analysis.

In conclusion, the result of this study indicate that RT3DE imaging during parabolic flight

is feasible and provides the basis for accurate quantification of LV volume changes with gravity,

thus providing pyramidal datasets from which correct non-foreshortened apical views can be

obtained. Moreover, also LA volume changes during weightlessness can be quantified by

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RT3DE. In microgravity, we reported an increase of both LV and LA volumes, due to changes in

venous return, which was counteracted by low body negative pressure.

Acknowledgements

We acknowledge the support from the Centre National d'Etudes Spatiales (CNES) and the

European Space Agency (ESA). We acknowledge the dedicated collaboration of the crew of

CNES AIRBUS A300 ZERO-G operated by NOVESPACE.

The invaluable support of Steve Anderson, Heinrich Beckermann, Stephane Husson and Arnoud

Perrin from Philips Medical Systems is appreciated.

Grants

Pierre Vaïda was the recipient of grant 02/CNES/4800000039 from the CNES.

Disclosures

Philips Medical Systems provided an equipment grant as well as a grant-in-aid to support this

project.

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Figure legends

Figure 1. Left: parabolic flight trajectory (black line) and corresponding gravity (Gz) along the

parabola (gray dashed line). Right: Experimental set-up onboard the Airbus. On the left, in

the foreground the LBNP chamber and in the background the ultrasound equipment

embedded into a safety rack. On the right, a bench and straps on the floor utilized to stabilize

the sonographer to prevent free floating during microgravity.

Figure 2. Left ventricular (LV) volume analysis procedure (see text for details): A) LV long-axis

and 6 equi-angled 2D cut-planes selection; B) semi-automatic tracing of the LV endocardial

contour in each cut-plane; C) automated computation of the 3D cast representing the LV

cavity volume.

Figure 3. Left atrial (LA) volume analysis procedure: A) LA long-axis and 8 equi-angled 2D cut-

planes selection; B and C) semi-automatic tracing of the LV endocardial contour in each set

of two orthogonal cut-planes; D) automated computation of the 3D cast representing LA

cavity volume.

Figure 4. Left ventricular (LV) volume vs time curves (top panel) and corresponding first

derivatives (bottom panel), both expressed in % of the heart cycle, obtained from a subject

during the first three gravity (Gz) phases of the parabola.

Figure 5. Left ventricular (LV) and left atrial (LA) 3D casts obtained from the same subject,

visualized using the same zooming scale and orientation, during the different gravity phases

of the parabola. In each cast, end-diastolic (light gray) and end-systolic (white shaded)

volumes are shown contemporaneously using transparency.

Figure 6. Average±SD of left ventricular (LV) parameters measured in 14 subjects during the

different gravity phases (0 Gz: microgravity; 1Gz: normogravity; 1.8 Gz: hypergravity; 1.8 Gz

end: second hypergravity phase) along the parabola (*: p<0.05 vs 1Gz; #: p<0.05 vs 0Gz).

All data in each subject have been normalized to the corresponding 1Gz value. EDV: end-

diastolic volume; ESV: end-systolic volume; SV: stroke volume; EF: ejection fraction; PFR:

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peak filling rate; PER: peak ejection rate.

Figure 7. Average±SD of left atrial (LA) parameters measured in 14 subjects during the different

gravity phases (0 Gz: microgravity; 1Gz: normogravity; 1.8 Gz: hypergravity; 1.8 Gz end:

second hypergravity phase) along the parabola (*: p<0.05 vs 1Gz; #: p<0.05 vs 0Gz). All

data in each subject have been normalized to the corresponding 1Gz value. LAmax: LA

volume at end-systole; LAmin: LA volume at end-diastole; FV: filling volume; DEI: diastolic

emptying index; EI: expansion index.

Figure 8. Average±SD of left ventricular (top) and left atrial (bottom) parameters measured in 10

subjects during the microgravity (0Gz) phase of the parabola without (OFF) and with (ON)

low body negative pressure at –50mmHg activated (*: p<0.05). EDV: end-diastolic volume;

ESV: end-systolic volume; SV: stroke volume; EF: ejection fraction; PFR: peak filling rate;

PER: peak ejection rate; LA: left atrial; LAmax: LA volume at end-systole; LAmin: LA volume

at end-diastole; FV: filling volume; DEI: diastolic emptying index; EI: expansion index.

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Table 1. Mean values ±SD of the left ventricular (LV) and atrial (LA) function parameters

computed in 14 normal subjects during the four phases of the parabola. In parenthesis the mean

percentage of variation in respect of 1 Gz value is reported.

Phase I (1 Gz) Phase II (1.8 Gz) Phase III (0 Gz) Phase IV (1.8 Gz)

LV EDV (ml) 87±22 72±29** (-19%) 105±32** (+19%) 81±29 (-9%)

LV ESV (ml) 29±9 23±13* (-24%) 35±13* (+23%) 24±13 (-21%)

LV SV (ml) 58±19 49±21* (-16%) 69±25** (+20%) 57±23 (-2%)

LV EF (%) 66±8 68±10 (+4%) 66±8 (0%) 70±10 (+6%)

LV PFR (ml/sec) 255±65 221±70 (-13%) 335±102* (31%) 278±89 (+8%)

LV PER (ml/sec) -325±120 -289±122 (-5%) -417±128* (37%) -431±192 (+30%)

LAmax (ml) 40±12 26±9* (-34%) 58±14** (+41%) 34±17 (-16%)

LAmin (ml) 18±5 13±4** (-29%) 23±9** (+26%) 15±7 (-17%)

LAmax-LAmin (ml) 21±8 13±5* (-36%) 35±7** (+59%) 19±12 (-18%)

DEI (%) 53±8 49±8 (-5%) 60±7* (+16%) 51±19 (-5%)

EI (%) 117±42 101±35 (-6%) 158±44* (+31%) 133±92 (+6%)

EDV: end-diastolic volume; ESV: end-systolic volume; SV: stroke volume; EF: ejection fraction; PFR: peak filling rate; PER: peak ejection rate; LAmax: left atrial volume at ventricular end-systole; LAmin: left atrial volume at ventricular end-diastole; DEI: diastolic emptying index; EI: expansion index. *: p<0.05 vs 1 Gz; **: p<0.01 vs 1Gz #: p<0.05 vs 0 Gz

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Table 2. Mean values ±SD of the left atrial diameters (D1, medial-lateral dimension; D2, antero-

posterior dimension) computed in 14 normal subjects at normogravity (1 Gz) and during

microgravity (0 Gz). In parenthesis the mean percentage of increase in respect of 1 Gz value is

reported.

Phase I (1 Gz) Phase III (0 Gz)

LAmax D1 (mm) 26±5 33±6* (28%)

LAmax D2 (mm) 42±7 49±8* (22%)

LAmin D1 (mm) 18±4 21±9 (32%)

LAmin D2 (mm) 32±8 39±9* (25%)

LAmax: left atrial volume at ventricular end-systole; LAmin: left atrial volume at ventricular end-diastole; DEI: diastolic emptying index; EI: expansion index. *: p<0.05 vs 1 Gz

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Figure 1

Phase II(1.8Gz)20 sec

Phase III(0Gz)24 sec

Phase IV(1.8Gz)20 sec

28,000 ft(8500 m)

20,000 ft(6100 m)

Phase I(1Gz)2min

Alti

tude

Gravity (G

z)

1.8

1

0

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Figure 2

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Figure 3

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Figure 4

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Figure 5

Phase I Phase II Phase III Phase IV

LV

LA

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EDV ESV

SV EF

0Gz 1Gz 1.8Gz end1.8Gz Figure 6

*

*#

#

*

*##

*

*#

#

PFR PER

*

#

#

*

#

N=14

0.6

1.6

1.0

% 1

Gz

valu

e

0.6

1.6

1.0

% 1

Gz

valu

e

0.4

2.0

1.0

% 1

Gz

valu

e

0.4

2.0

1.0

% 1

Gz

valu

e

0Gz 1Gz 1.8Gz end1.8Gz

0.6

1.6

1.0

% 1

Gz

valu

e

0.4

1.6

1.0

% 1

Gz

valu

e

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LAmax LAmin

FV DEI

Figure 7

*

*#

#

*

*#

#

*

*##

*

EI

*

#

N=14

0.4

1.8

1.0

% 1

Gz

valu

e

0.2

2.0

1.0

% 1

Gz

valu

e

0.2

2.0

1.0

% 1

Gz

valu

e

0.2

2.0

1.0

% 1

Gz

valu

e

0.4

1.8

1.0

% 1

Gz

valu

e



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% 1

Gz

valu

e

0,4

0,6

0,8

1,0

1,2

1,4

1,6

1,8

2,0

OFF ON OFF ON OFF ON OFF ON OFF ON

* **

LAmax LAmin FV DEI EI

% 1

Gz

valu

e

0,4

0,6

0,8

1,0

1,2

1,4

1,6

1,8

2,0

OFF ON OFF ON OFF ON OFF ON OFF ON

* **

LAmax LAmin FV DEI EI

% 1

Gz

valu

e

0,4

0,6

0,8

1,0

1,2

1,4

1,6 EDV ESV

OFF ON

SV PFR PER

* *

EF

OFF ON OFF ON OFF ON OFF ON OFF ON Figure 8

N=10

N=10

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